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Compound Alzheimer’s Drug Could Regenerate Lost Brain Connections

Written by Rachel Barclay
| Published on June 18, 2013

A decade-long study sheds light on how Alzheimer’s disease damages the brain, and results in a new drug that can reverse the damage.

A new drug, called NitroMemantine, combines twomedicines
that are already FDA-approved to create an anti-Alzheimer's super-drug.
Unlike most existing Alzheimer’s treatments, NitroMemantine appears to
directly target the cellular pathway that causes patients with
Alzheimer’s disease to lose important brain connections.

Alzheimer’s disease is one of the leading causes of dementia, affecting approximately five million Americans
today. With the ever-growing cost of providing care for ailing seniors,
drugs that can offset dementia and keep people healthy into old age are
a researcher's dream.

Out With the Old, in With the New

Most
of what doctors currently know about Alzheimer’s disease comes from
observation. Scientists can autopsy the brain of a patient who has
passed away from Alzheimer’s and examine tissue samples under a
microscope. On that level, the disease is very apparent: clusters of
proteins called amyloid beta plaques and neurofibrillary tangles clog
the brain, interfering with its ability to send information from one
area to another through structures called synapses.

The cause
seems obvious—these protein clumps poison or otherwise damage the brain
cells that transmit information, called neurons. Drug after drug has
been developed to break apart these clumps or prevent them from forming
in the first place, but they've met with little success.

"We took a
different tack. We said, let's protect the synapses," said Lipton,
Scientific Director of Sanford-Burnham and a clinical neurologist at the
University of California, San Diego.

Lipton
noticed that the damaged cells had high levels of a neurotransmitter
chemical called glutamate, a molecule that neurons use to talk to one
another. Researchers in the past had assumed this was a result of damage
caused by the plaques and tangles, but Lipton thought glutamate might
play an active role in neural deterioration.

"The only
pathological correlate with how demented one becomes in Alzheimer's is
the number of synapses," Lipton explained. "You can have a lot of
amyloid protein and not a lot of cognitive deficit."

Through a
robust series of experiments in living rats and human brain cells grown
in the lab, Lipton’s team seems to have found the answer.

Lipton
discovered that the compound drug NitroMemantine not only completely
eliminated the loss of synapses caused by the amyloid proteins, but even
reversed it. Within six hours, cells were regrowing synapses that had
already been lost to Alzheimer's, and the effect was apparent only ten
minutes after administering the drug.

The Brain’s Worst Enemy: Itself

Less
than one brain cell in ten is a neuron. The rest are cells called glia,
which help neurons transmit information faster, protect them from
toxins and infections, and perform other vital functions. One type of
glial cell is called an astrocyte.

Astrocytes wrap around neurons
to protect them. Unlike most of the body’s cells, which can grow back if
they die, most of the brain can't grow new cells in adulthood, making
protecting existing cells high a priority. By standing between the
bloodstream and the neuron they are protecting, astrocytes can filter
out any toxins a person might consume in his or her diet and also act as
a first line of defense against invading viruses and bacteria.

For
more than a century, scientists thought the role of astrocytes was
solely protective. New research, including Lipton’s, has shown that
astrocytes play a much greater part than previously thought.

Even
small amounts of amyloid protein were enough to activate an astrocyte,
the researchers found. The astrocytes began releasing glutamate and
activating a specific receptor on the neuron they were protecting.
Although the exact mechanism is unknown, in each of their trials,
Lipton’s team observed the same results: when these glutamate receptors
were activated on a neuron, the neuron began to lose its connections and
ability to communicate.

An average neuron in the brain has 10,000
connections to other neurons. If a neuron is starved for communication,
as is the case in Alzheimer's patients, the neuron will eventually
wither and die.

So why do astrocytes cause the brain to lose these
key connections? Besides protecting neurons, one of their purposes is
to keep the growth of the brain in check. Having too many neural
connections has been tied to, among other things, depression,
schizophrenia, and bipolar disorder. By preventing overgrowth,
astrocytes help keep the brain healthy. In the case of Alzheimer’s,
however, it appears this regulation system is overactive and prunes away
too many connections.

This is where NitroMemantine comes into play.

Memantine,
a drug that is already FDA-approved to treat Alzheimer’s disease, can
block glutamate receptors without activating them, so that the glutamate
released by the astrocyte has nowhere to go. However, memantine has a
strong positive charge, making it slide away from the receptor as if you
were trying to force together the south ends of two magnets. This is
why drug trials of memantine alone have not proven particularly
effective.

Lipton’s team added on a nitro group, taken from
another drug called nitroglycerin, which is widely used to treat heart
conditions. The nitro group has a strong attraction to the glutamate
receptor, allowing memantine to reach the right location and protect the
neuron.

Even better, NitroMemantine targets just the glutamate
receptors that astrocytes use, and leaves alone the receptors that
neurons need to continue communicating with each other.

"The FDA-approved drug memantine, which we previously developed,
targets sick nerve cells," Lipton said. "The more disease there is, the
better the drug works. These drugs are only there when you need them
and when they're done, they leave."

If NitroMemantine proves as
effective in living humans as it has in the lab, it could be the first
drug to prevent and reverse Alzheimer’s-related brain damage. If
Alzheimer’s is caught early enough, with this drug, the patient might
never experience dementia at all.

"Now, rather than just barely protecting synapses, at least in the animal models, the new improved drug, NitroMemantine, gets the number of synapses all the way back to normal,"
Lipton said. "That was really a surprise. That gives me hope that
there's really something here, but there's a lot more work to be done."

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